Highly Regioselective Synthesis of Oxindolyl-Pyrroles and Quinolines

Mar 9, 2018 - Srinivasarao Yaragorla , Ravikrishna Dada, P. Rajesh, and Manju Sharma. School of Chemistry, University of Hyderabad, P.O. Central ...
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Article Cite This: ACS Omega 2018, 3, 2934−2946

Highly Regioselective Synthesis of Oxindolyl-Pyrroles and Quinolines via a One-Pot, Sequential Meyer−Schuster Rearrangement, AntiMichael Addition/C(sp3)−H Functionalization, and Azacyclization Srinivasarao Yaragorla,* Ravikrishna Dada, P. Rajesh, and Manju Sharma School of Chemistry, University of Hyderabad, P.O. Central University, Hyderabad 500046, India S Supporting Information *

ABSTRACT: A one-pot, sequential Meyer−Schuster (MS) rearrangement of oxindole-derived propargyl alcohols to the corresponding α,β-unsaturated enones and their anti-Michael addition, followed by intramolecular azacyclization is described in a highly regioselective manner using Ca(OTf)2 as the promoter. Further, we described the one-pot MS rearrangement, followed by C(sp3)−H functionalization of 2-methyl azaarenes at α-carbon of these doubly activated alkenes. Control experiments and computational calculations were performed to propose the reaction mechanism.

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INTRODUCTION 1,4-Conjugate addition (the Michael addition) of a nucleophile to the α,β-unsaturated systems (Michael acceptors) is one of the most versatile and fundamental carbon−carbon bond forming reactions in organic synthesis.1 As depicted in Figure 1,

In recent years, Meyer−Schuster (MS) rearrangement, that is, the conversion of propargyl alcohols to activated olefins (Michael acceptors), has become an attractive reaction because of its simple operation and atom economy.6−9 Although the diverse range of α,β-unsaturated systems are retrieved through MS rearrangement, isatin-derived Michael acceptors have not yet been synthesized from the corresponding propargyl alcohols through MS rearrangement. It is interesting to note that these compounds are known to react in a conjugate addition.10 Hence, we were interested to develop the first synthesis of such doubly activated olefins through the MS rearrangement and a conjugate addition of these products through the one-pot approach. In continuation of our research interests toward the use of propargyl alcohols as suitable synthons for the synthesis of privileged molecules,11 herein, we report our investigations on the cascade synthesis of 3-pyrrolylindolin-2-ones and 3-azarenyl-indolin-2-ones through a one-pot MS rearrangement, anti-Michael addition, and intramolecular azacyclization sequence.

Figure 1. Schematic representation of Michael and anti-Michael addition.

the usual Michael addition of a nucleophile to the α,βunsaturated systems yields the adduct with β-substitution. However, if the substrate has a strong electron-withdrawing group at the β-position, then the Michael addition can be circumvented, which may lead to the regiospecific addition at the α-carbon (Figure 1). Thus, the addition of a nucleophile to the α-carbon of an α,β-unsaturated system is commonly known as anti-Michael addition, contra-Michael addition, or abnormal Michael reaction.2 In fact, the addition of nucleophiles to α,βunsaturated systems in which strong electron-withdrawing substituents redirect the polarity of the double bonds at βcarbon is also a Michael addition concerning the strong electron-withdrawing group and double bond portion as the Michael acceptor. This concept has been explored under suitable conditions on systems with double bonds activated on both sides, and as a result, few synthetic studies and computational reports are available on anti-Michael addition.2−5 © 2018 American Chemical Society

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RESULTS AND DISCUSSION We chose 3-hydroxy-3-(phenylethynyl)indolin-2-one (1a) as the model substrate for the MS rearrangement reaction. Initially, 1a was refluxed in 1,2-dichloroethane (DCE) in the presence of 10 mol % of Ca(OTf)2 and Bu4NPF6 (additive) for 12 h, but no reaction was observed (entry 1, Table 1). Indeed, the same is the case with other solvents, such as toluene and water, under reflux conditions (entries 2 and 3). Interestingly, when we switch the solvent to ethanol and reflux the propargyl alcohol 1a with 10 mol % of Ca(OTf)2 and Bu4NPF6 (additive) Received: January 24, 2018 Accepted: February 27, 2018 Published: March 9, 2018 2934

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ACS Omega Table 1. Optimization of MS Rearrangement of Oxindole-Derived Propargyl Alcohol 1a to 2a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

catalyst (mol %) Ca(OTf)2/Bu4NPF6, Ca(OTf)2/Bu4NPF6, Ca(OTf)2/Bu4NPF6, Ca(OTf)2/Bu4NPF6, Ca(OTf)2/Bu4NPF6, Ca(OTf)2/Bu4NPF6, Ca(OTf)2/Bu4NPF6,

(10/10) (10/10) (10/10) (10/10) (10/10) (10/10) (10/10)

Ca(OTf)2, (10) Bu4NPF6, (10) Ca(OTf)2/Bu4NPF6, (10/5) Ca(OTf)2/Bu4NPF6, (5/10) Mg(OTf)2/Bu4NPF6, (10/10) Cu(OTf)2, (10) p-TSA, (10)

reaction conditions

yield (%)

1,2-DCE, 90 °C, 12 h toluene, 110 °C, 12 h water, 100 °C, 12 h EtOH, 90 °C, 12 h MeOH, 65 °C, 12 h isopropanol, 90 °C, 6 h isobutanol, 90 °C, 4 h isobutanol, 90 °C, 6 h isobutanol, 90 °C, 8 h isobutanol, 90 °C, 8 h isobutanol, 90 °C, 4 h isobutanol, 90 °C, 4 h isobutanol, 90 °C, 8 h isobutanol, 90 °C, 8 h isobutanol, 90 °C, 8 h

nr nr nr 60 63 78 93 nr 35 nr 80 60 40 nr 70

Scheme 1. Substrate Scope of Oxindole-Derived Propargyl Alcohols in Ca(II)-Catalyzed MS Rearrangement

minimize the catalyst loadings were unsuccessful, as shown in Table 1 (entries 11 and 12). The reaction with other catalysts such as Mg(OTf)2 gave the poor yield of 2a (entry 13), ptoluenesulfonic acid (TSA) gave a moderate yield of 70% (entry 15), and Cu(OTf)2 was found to be ineffective (entry 14). Finally, entry 7 was found to be the optimum condition for the MS rearrangement of 1a to 2a. After establishing the suitable conditions for the MS rearrangement, we explored the scope of this protocol to a diverse range of oxindole-derived propargyl alcohols, and the results are summarized in Scheme 1. The MS rearrangement reaction showed an excellent substrate scope concerning the substitution of the benzene ring of oxindole, including 5methyl, 5-chloro, 5-fluoro, and 7-fluoro substitutions, and gave the enones 2a−e in good yields. Gratifyingly, the reaction also

for 12 h, MS rearrangement took place and furnished the enone 2a in 60% yield (entry 4). Encouraged by this result, we examined other alcoholic solvents, such as methanol, isopropanol, and isobutanol. The first two alcohols gave slightly better yields (entries 5 and 6); fortunately, the last one (isobutanol) gave 93% yield in 4 h (entry 7). After identifying the suitable solvent, we aimed to check the role of the Ca(II) catalyst in the rearrangement and hence 1a was refluxed in isobutanol without catalyst for 6 h (entry 8) and noted that the reaction could not initiate, which confirmed the need for a catalyst. Next, we performed a couple of experiments to see the importance of Ca(II) and additive combination. In the absence of additive Bu4NPF6, the reaction gave 35% yield of 2a (entry 9), and in the absence of Ca(OTf)2, the reaction could not even initiate (entry 10). Further experiments to 2935

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ACS Omega

Figure 2. Schematic representation of Meyer−Schuster (MS) rearrangement (current and previous).

Figure 3. NBO charge distribution on the activated C−C double bond.

Scheme 2. MS Rearrangement, Conjugate Addition, and C( (sp3)−H Functionalization Cascade

tolerated the N-alkyl substitutions of oxindole moiety, such as N-methyl, N-phenyl, N-benzyl, and N-allyl, and furnished the alkenes 2f−i, activated on both sides in good yields. The next possible diversity of this reaction is the alkyne moiety, and we are glad to see that when the phenyl alkyne was changed to (4methyl)-phenyl, (4-methoxy)-phenyl group, the reaction showed a similar reactivity and yielded the products 2j−m in good yields. It is worth noting that not only aryl alkynes but also aliphatic alkynes, such as cyclohexyl alkyne and n-pentyne, took part in the MS rearrangement and resulted in the respective products 2n and 2o in moderate yield. Encouraged by the broad substrate scope of Ca(II)-catalyzed MS rearrangement of oxindole-derived propargyl alcohols (Scheme 1), we were then interested in trapping these activated olefins into a one-pot, tandem reaction. It is to highlight that, so far there is no report available on the MS

rearrangement of oxindole-derived propargyl alcohols followed by the one-pot, sequential synthetic reaction. As depicted in Figures 1 and 2, these activated enones are perfect ambident substrates and can undergo two possible modes of conjugate additions, namely, Michael addition and conjugate addition. Interestingly, the observed products are entirely regiospecific. However, the reason for this behavior is not thoroughly investigated. Therefore, we planned for the systematic investigations and theoretical calculations to explain the regiospecificity and hence designed the one-pot, sequential reactions starting from propargyl alcohols. The natural bond orbital (NBO) charge distribution of selected compounds (2a, 2c, 2e, 2f, 2n, and 2o) was studied by performing ab initio (B3LYP/6-31g**) calculations. The results indicate that the nucleophilic addition is more preferred at α-carbon over β-carbon (Figure 3). To check this 2936

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ACS Omega Scheme 3. One-Pot, Sequential MS Rearrangement, Conjugate Addition, and C(sp3)−H functionalizationa

a Reaction conditions: all reactions are carried out with 1 equiv of 1; refluxed in minimum solvent; after MSR, 1.2 equiv of 3 was added; and the temperature was raised to 110 °C.

Scheme 4. Execution of One-Pot, Sequential MS Rearrangement, Anti-Michael Addition, and Azacyclization

experimentally, we chose 2-methyl quinoline as the nucleophile because oxindole and quinolines are privileged molecules, so the combination (hybrid) of these two privileged molecules would be of more medicinal importance.12 On the basis of this assumption, 1a was subjected to MS rearrangement and then quinoline 3a was added to the reaction and continued for 12 h; gratifyingly, 61% yield of 4a was obtained in a one-pot, sequential MS rearrangement, conjugate addition,13 and C(sp3)− H functionalization sequence (Scheme 2). With the success of the one-pot synthesis of 3-(1-oxo-1phenyl-3-(quinolin-2-yl)propan-2-yl)indolin-2-one (4a) from propargyl alcohol 1a, we were interested to see the generality of this sequential reactions, and as a result, we synthesized 4b in 72% yield with 1a and 7-chloro quinaldine (Scheme 3). Similarly, other oxindole-derived propargyl alcohols also showed excellent reactivity toward quinaldine and 7-chloroquinaldine and furnished the respective compounds 4c−f (Scheme 3) in moderate to good yields. With a precedent established by the success of one-pot, sequential reactions between 1 and 3, we planned to explore the possibility of intramolecular annulation strategy to this sequential one-pot procedure. In this regard, oxindoles bearing

densely substituted pyrroles at 3-position were attracted the attention owing to their privileged nature.14,10b So, we aimed the synthesis of these molecules from propargyl alcohols: compound 1a was subjected to standard conditions of MS rearrangement, and then, aniline and ethyl acetoacetate were added to the reaction mixture and the reaction was continued for 9 h to obtain the desired product 7a in 75% overall yield (Scheme 4). The substrate scope of this one-pot, three-component synthesis of oxindol-3-yl-pyrroles is further investigated; the reaction finds quite generous with respect to propargyl alcohols (1), β-keto esters (5), and various amines (6); and the results are tabulated in Table 2. For example, propargyl alcohol 1a and ethyl acetoacetate (5a) react with aniline (6a) and benzyl amines (6b) to yield 7a and 7b in good yields. Methyl acetoacetate also showed excellent reactivity with 1a and 6a, 6b to furnish 7c and 7d in respective yields of 73 and 81%. Not only aryl amines but also aliphatic amines reacted in this onepot synthesis and furnished the respective products in good yields. In case of cyclic β-keto esters, the reaction worked but gave poor yields of 7w and 7x, probably because the rigidity of the cyclic structure slows down the azacyclization step. In case 2937

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ACS Omega Table 2. Substrate Scope of Ca(II)-Catalyzed One-Pot Synthesis of Oxindolyl-Pyrrolesa

a

Reaction condition: all reactions were carried out with 1 equiv of 1, in minimum amount of 2-butanol; after the MSR, 1 equiv of 5 and 1.1 equiv of 6 were added at 90 °C. A enaminoester was pregenerated and added.

of the compound ethyl 4-(2-oxoindolin-3-yl)-1,5-diphenyl-1Hpyrrole-3-carboxylate, the β-enaminoester was prepared separately from ethyl propiolate and aniline and then added to the in situ generated activated alkene and obtained in 58% yield.

Later, we performed the control experiments (Scheme 5) to understand the mechanism in detail; the reaction (one-pot, sequential MS rearrangement, conjugate addition, and azacyclization) of 1a under standard conditions (Scheme 5, eq i) 2938

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ACS Omega Scheme 5. Control Experiments

works through a stepwise addition, i.e., after noticing the MS rearrangement by thin-layer chromatography, aniline and ethylene−acrylic acid (EAA) should be added. However, it was observed that the mixing of the three reactants together in the presence of Ca(II) could not lead to the product, but only gave the enaminoester (eq ii) and even this enaminoester could add to 1a (eq iii). Mixing of 2a with aniline and EAA in the

presence of Ca(II) gave the product 7a (eq v), as well as proved that the conjugate addition is proceeding through the βenaminoester (eq vi), but not through alkylation of 2a with EAA, followed by condensation with aniline (eq viii). It also indicated that the catalyst is not required for the conjugate addition and annulation (eqs v and vi).14,15 However, the presence of a catalyst is compulsory for the MS rearrangement 2939

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ACS Omega Scheme 6. Possible Mechanism

Figure 4. Proposed intermediates of α-addition and β-addition.

of propargyl alcohol (Table 1, entry 8). On the basis of these observations, the mechanism for the one-pot synthesis of oxindolyl-pyrrole is presented in Scheme 6. Further to the NBO charge distribution calculations (Figure 3), we also investigated the experimentally observed formation of product 3 (via α-addition) by comparing the energies of intermediates α1 and β1, which would be formed by α and βadditions, respectively, as shown in Figure 4. The geometries of intermediates were optimized using Hartree−Fock (HF) level theory and 3-21g basis set. The single-point energy (B3LYP/631g**) calculations of the optimized structures show that intermediate α1 is stable by −17.37 kJ/mol compared to intermediate β1. Hence, we propose that the formation of enol in intermediate α1 provides extra stability due to enhanced aromaticity.

On the basis of these experimental and computational observations, we proposed the mechanism for this one-pot, sequential synthesis of oxindolyl-pyrroles from oxindolepropargyl alcohols (Scheme 6). In conclusion, we developed the first synthetic approach for the Meyer−Schuster rearrangement of isatin-derived propargyl alcohols to the corresponding α,β-unsaturated enones under calcium catalysis. Further, we utilized these activated olefins into one-pot, sequential reactions and synthesized the privileged molecules of medicinal importance, 3-pyrrolylindolin-2-ones, and 3-azaarenyl-indolin-2-ones with a broad substrate scope and good yields. This one-pot reaction involves the following sequence of reactions: Meyer−Schuster rearrangement, anti-Michael addition/C(sp3)−H functionalization, intramolecular azacyclization, and aromatization. Control 2940

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7.5 Hz, 2H), 7.89 (s, 1H), 7.56 (t, J = 7 Hz, 1H), 7.54 (t, J = 8 Hz, 2H), 7.33 (m, 1H), 7.03−7.01 (dd, J = 1.5, 8 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz): δ 191.1, 169.5, 143.3, 137.5, 136.7, 133.8, 132.7, 128.9, 128.8, 128.0, 126.4, 122.8, 120.7, 110.1 ppm; HRMS (ESI-TOF): m/z calcd for C16H11NO2 [M + H]+: 250.0867; found: 250.0864. 5-Methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (2b).15c Yield: 86 mg (86%) as orange solid; mp: 188−189 °C; 1 H NMR (MeOD-d4, 500 MHz): δ 8.13 (d, J = 6.0 Hz, 1H), 8.01 (d, J = 6.5 Hz, 2H), 7.89 (s, 1H), 7.77 (s, 1H), 7.39−7.32 (m, 3H), 6.96−6.89 (m, 2H), 2.44 (s, 3H) ppm; 13C NMR (MeOD-d4, 125 MHz): δ 191.1, 169.6, 145.1, 144.4, 136.5, 134.9, 132.3, 129.3, 128.5, 127.0, 126.1, 122.0, 120.3, 110.0, 20.3 ppm; HRMS (ESI-TOF): m/z calcd for C17H13NO2 [M + Na]+: 286.0844; found: 286.0841. 5-Chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one (2c).15c Yield: 89 mg (89%) as red solid; mp: 202−203 °C; 1H NMR (DMSO-d6, 500 MHz): δ 10.97 (s, 1H), 8.12−8.08 (m, 3H), 7.81 (s, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 8.0 Hz, 2H), 7.43−7.41 (dd, J = 2, 8 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 191.4, 168.3, 144.3, 137.4, 136.2, 137.7, 132.9, 129.6, 129.1, 127.6, 126.7, 126.0, 121.8, 112.3 ppm; HRMS (ESI-TOF): m/z calcd for C16H10ClNO2 [M + Na]+: 306.0298; found: 306.0296. 5-Fluoro-3-(2-oxo-2-phenylethylidene)indolin-2-one (2d).15e Yield: 71 mg (71%) as orange solid; mp: 187−188 °C; 1 H NMR (CDCl3, 500 MHz): δ 8.48 (s, 1H), 8.12 (t, J = 6.4 Hz, 3H), 7.95 (s, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.15−7.11 (m, 1H), 7.01−6.98 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz): δ 190.8, 168.4, 148.4 (d, J = 247 Hz, 1C-F), 145.9, 137.3, 135.9, 134.0, 129.0, 128.8, 128.0, 123.6, 123.2, 123.0, 119.4, 119.2, 111.5 ppm; IR (KBr): 1716, 1654, 1597, 1458, 1236, 1168 cm−1; HRMS (ESI-TOF): m/z calcd for C16H10FNO2 [M + H]+: 268.0774; found: 268.0778. 7-Fluoro-3-(2-oxo-2-phenylethylidene)indolin-2-one (2e).15a Yield: 73 mg (73%) as orange solid; mp: 182−183 °C; 1 H NMR (CDCl3, 500 MHz): δ 8.29 (s, 1H), 8.12 (t, J = 7.0 Hz, 2H), 7.94 (s, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 8.5 Hz, 2H), 6.99 (d, J = 5.5 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz): δ 190.8, 168.4, 147.4 (d, J = 255 Hz, 1C-F), 137.3, 134.0, 129.0, 128.8, 128.7, 128.0, 123.6, 123.2, 123.0, 119.4, 119.2 ppm; HRMS (ESI-TOF): m/z calcd for C16H10FNO2 [M + H]+: 268.0774; found: 268.0778. 1-Methyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (2f).15b Yield: 85 mg (85%) as red solid; mp: 101−102 °C; 1H NMR (CDCl3, 500 MHz): δ 8.31 (d, J = 7.5 Hz, 1H), 8.11− 8.09 (dd, J = 1.0 and 8.0 Hz, 2H), 7.89 (s, 1H), 7.64−7.61 (m, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.39−7.35 (m, 1H), 7.03−7.01 (dd, J = 1.5 and 7.5 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 191.1, 167.9, 146.0, 137.6, 136.5, 133.7, 132.5, 128.9, 128.8, 127.6, 126.3, 122.8, 120.1, 108.1, 26.3 ppm. 3-(2-Oxo-2-phenylethylidene)-1-phenylindolin-2-one (2g). Yield: 71 mg (71%) as orange solid; mp: 118−119 °C; 1H NMR (CDCl3, 400 MHz): δ 8.35 (d, J = 7.6 Hz, 1H), 8.17− 8.15 (dd, J = 1.2 and 6.4 Hz, 2H), 8.00 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.60−7.55 (m, 4H), 7.48−7.45 (m, 3H), 7.30 (t, J = 7.6 Hz, 1H), 7.10−7.08 (dd, J = 1.2 and 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H) ppm; 13C NMR (CDCl3, 125 MHz): δ 191.3, 167.3, 145.9, 137.5, 136.3, 134.0, 133.9, 132.5, 129.7, 128.9, 128.8, 128.3, 127.7, 127.1, 126.6, 123.2, 120.1, 109.6 ppm; IR (KBr): 1711, 1655, 1608, 1453, 1329, 1231 cm−1; HRMS (ESI-

experiments and computational calculations were performed to describe the feasibility and path of the reaction mechanism.

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EXPERIMENTAL SECTION General Information. Unless otherwise noted, the chemicals and solvents purchased were of high-purity commercial grade and used without further purification. Thin-layer chromatography was performed on Merck precoated silica gel plates (60 F254) using UV light as a visualizing agent. Silica gel (60−120 mesh) was used for column chromatography. 1H NMR and 13C NMR spectra were recorded at 500, 400 and 125, 100 MHz, respectively, in CDCl3, dimethyl sulfoxide (DMSO)-d6, and MeOD-d4 using an internal reference on an Bruker Avance spectrometer. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q = quartet, and m = multiplet. High-resolution mass spectra (HRMS) were recorded using electrospray ionization time-of-flight (ESITOF) mass spectrometry (ESI-MS). Melting points were measured with a MEPA Lab (India) melting point apparatus. General Experimental Procedure for the Synthesis of Phenacylideneindolin-2-one 2a. To a 10 mL flask were successively added the respective propargylic alcohol 1a (100 mg, 0.40 mmol), Ca(OTf)2 (13.5 mg, 0.04 mmol), Bu4NPF6 (15.5 mg, 0.04 mmol), and 3 mL of isobutanol. The resulting mixture was stirred at 90 °C until almost full consumption of 1a as monitored by thin-layer chromatography, and then, the solvent was evaporated by vacuum and the reaction mixture was directly subjected to flash column chromatography on silica gel using 20−30% petroleum ether/ethyl acetate to afford the corresponding product 2a (93 mg, 93%). General Experimental Procedure for the Synthesis of 3-(1-Oxo-1-phenyl-3-(quinolin-2-yl)propan-2-yl)indolin2-one 4a. To a 10 mL flask were successively added the respective propargylic alcohol 1a (100 mg, 0.40 mmol), Ca(OTf)2 (13.5 mg, 0.04 mmol), Bu4NPF6 (15.5 mg, 0.04 mmol), and 3 mL of isobutanol. The resulting mixture was stirred at 90 °C until almost full consumption of 1a as monitored by thin-layer chromatography, and then, the respective quinaldine 3a (68.9 mg, 0.48 mmol) was added. The resulting mixture was refluxed at 110 °C until the formation of product, and then, the solvent was evaporated by vacuum and the reaction mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the corresponding product 4a (96 mg, 61%). General Experimental Procedure for the Synthesis of Ethyl 2-Methyl-4-(2-oxoindolin-3-yl)-1,5-diphenyl-1Hpyrrole-3-carboxylate 7a. To a 10 mL flask were successively added the respective propargylic alcohol 1a (100 mg, 0.40 mmol), Ca(OTf)2 (13.5 mg, 0.04 mmol), Bu4NPF6 (15.5 mg, 0.04 mmol), and 3 mL of isobutanol. The resulting mixture was stirred at 90 °C until almost full consumption of 1a as monitored by thin-layer chromatography, and then, the respective 1,3-diketone 5a (52 mg, 0.40 mmol) and amine 6a (41 mg, 0.44 mmol) were added. The resulting mixture was stirred at 80 °C until the formation of product, and then, the solvent was evaporated by vacuum and the reaction mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/ethyl acetate) to afford the corresponding product 7a. 3-(2-Oxo-2-phenylethylidene)indolin-2-one (2a).9e Yield: 93 mg (93%) as red solid; mp: 192−193 °C; 1H NMR (CDCl3, 500 MHz): δ 8.56 (s, 1H), 8.33 (d, J = 7.5 Hz, 1H), 8.13 (d, J = 2941

DOI: 10.1021/acsomega.8b00147 ACS Omega 2018, 3, 2934−2946

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ACS Omega TOF): m/z calcd for C22H15NO2 [M + Na]+: 348.1001; found: 348.1006. 1-Benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (2h).15f Yield: 83 mg (83%) as red solid; mp: 123−124 °C; 1H NMR (CDCl3, 500 MHz): δ 8.34 (d, J = 7.5 Hz, 1H), 8.16− 8.14 (dd, J = 1.5 and 8.0 Hz, 2H), 7.98 (s, 1H), 7.65 (d, J = 7 Hz, 1H), 7.56 (t, J = 7.0 Hz, 2H), 7.35−7.27 (m, 6H), 7.03− 7.01 (dd, J = 1.5 and 7.5 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.00 (s, 2H) ppm; 13C NMR (CDCl3, 125 MHz): δ 191.2, 168.1, 145.1, 137.5, 136.3, 135.4, 133.8, 132.5, 128.9, 128.8, 127.9, 127.8, 127.7, 127.2, 126.7, 122.8, 120.2, 109.2, 43.9 ppm; HRMS (ESI-TOF): m/z calcd for C23H17NO2 [M + Na]+: 362.1157; found: 362.1156. 1-Allyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (2i).15f Yield: 86 mg (86%) as wine red solid; mp: 93−94 °C; 1H NMR (CDCl3, 400 MHz): δ 8.32 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.93 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.63−7.53 (m, 2H), 7.37−7.35 (dd, J = 1.2 and 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.91−5.85 (m, 1H), 5.31−5.25 (m, 2H), 4.43−4.41 (m, 2H) ppm; 13C NMR (CDCl3, 100 MHz): δ 191.2, 167.6, 145.2, 137.5, 136.3, 133.8, 132.5, 131.1, 128.9, 128.8, 127.7, 126.5, 122.8, 120.1, 117.7, 109.1, 42.4 ppm; HRMS (ESI-TOF): m/z calcd for C19H15NO2 [M + Na]+: 312.1001; found: 312.1001. 3-(2-Oxo-2-(p-tolyl)ethylidene)indolin-2-one (2j).15d Yield: 91 mg (91%) as orange solid; mp: 203−204 °C; 1H NMR (CDCl3, 500 MHz): δ 8.28 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.34−7.31 (m, 3H), 7.01 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H) ppm; 13 C NMR (CDCl3, 125 MHz): δ 190.7, 169.2, 144.9, 143.0, 136.2, 135.1, 132.5, 129.6, 128.9, 127.9, 126.9, 122.8, 120.7, 110.0, 21.8 ppm; HRMS (ESI-TOF): m/z calcd for C17H13NO2 [M + H]+: 264.1024; found: 264.10212015. 3-(2-(4-Methoxyphenyl)-2-oxoethylidene)indolin-2-one (2k).15d Yield: 81 mg (81%) as red solid; mp: 238−239 °C; 1H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 8.07−8.05 (dd, J = 2.0 and 7.6 Hz, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.35−7.30 (m, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.96−6.87 (m, 2H), 3.87 (s, 3H) ppm; 13C NMR (DMSO-d6, 100 MHz): δ 190.1, 168.6, 164.4, 145.2, 136.0, 133.0, 131.6, 130.3, 127.1, 126.9, 122.1, 120.4, 114.9, 110.7, 56.1 ppm; HRMS (ESITOF): m/z calcd for C17H13NO3 [M + Na]+: 302.0793; found: 302.0789. 5-Methyl-3-(2-oxo-2-(p-tolyl)ethylidene)indolin-2-one (2l). Yield: 84 mg (84%) as wine red solid; mp: 166−167 °C; 1H NMR (DMSO-d6, 500 MHz): δ 10.69 (s, 1H), 7.97 (d, J = 8 Hz, 2H), 7.86 (s, 1H), 7.67 (s, 1H), 7.41 (d, J = 8 Hz, 2H), 7.16−7.15 (dd, J = 1 and 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 2.41 (s, 3H), 2.21 (s, 3H) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 191.1, 168.7, 145.1, 143.0, 136.9, 135.1, 133.7, 130.8, 130.1, 129.1, 127.5, 126.3, 120.5, 110.5, 21.7, 21.1 ppm; IR (KBr): 1717, 1660, 1598, 1463, 1360, 1221 cm−1; HRMS (ESITOF): m/z calcd for C18H15NO2 [M + Na]+: 300.1001; found: 300.1001. 5-Chloro-1-methyl-3-(2-oxo-2-(p-tolyl)ethylidene)indolin2-one (2m).9e Yield: 79 mg (79%) as orange solid; mp: 183− 184 °C; 1H NMR (CDCl3, 500 MHz): δ 8.37 (s, 1H), 8.01 (d, J = 8 Hz, 2H), 7.93 (s, 1H), 7.34 (d, J = 8 Hz, 3H), 6.74 (d, J = 8.5 Hz, 1H), 3.26 (s, 3H), 2.46 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 190.2, 167.5, 145.1, 144.3, 135.4, 135.0, 132.0, 129.6, 128.9, 128.2, 127.8, 127.7, 121.3, 109.0, 26.3, 21.8 ppm; HRMS (ESI-TOF): m/z calcd for C18H14ClNO2 [M + Na]+: 334.0611; found: 334.0611.

3-(2-Cyclohexyl-2-oxoethylidene)indolin-2-one (2n). Yield: 61 mg (61%) as red solid; mp: 164−165 °C; 1H NMR (CDCl3, 500 MHz): δ 8.52 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.35−7.32 (m, 1H), 7.25 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 2.70−2.65 (m, 1H), 2.01−1.99 (m, 2H), 1.87−1.83 (m, 2H), 1.74−1.71 (m, 1H), 1.46−1.35 (m, 5H) ppm; 13C NMR (CDCl3, 125 MHz): δ 204.1, 169.3, 143.0, 135.7, 132.7, 128.3, 127.5, 122.9, 120.8, 109.8, 52.1, 28.2, 25.7, 25.5 ppm; IR (KBr): 1710, 1654, 1602, 1463, 1329, 1225 cm−1; anal. calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49; found: C, 75.36; H, 6.68; N, 5.54. 3-(2-Oxopentylidene)indolin-2-one (2o). Yield: 66 mg (66%) as pale brown solid; mp: 171−172 °C; 1H NMR (CDCl3, 400 MHz): δ 8.56 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 2.75 (t, J = 7.2 Hz, 2H), 1.80−1.74 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 201.2, 169.8, 143.3, 135.4, 132.9, 128.4, 127.7, 122.9, 120.7, 110.0, 46.9, 17.4, 13.6 ppm; IR (KBr): 1711, 1644, 1598, 1453, 1329, 1221 cm−1; anal. calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51; found: C, 72.60; H, 6.01; N, 6.54. 3-(1-Oxo-1-phenyl-3-(quinolin-2-yl)propan-2-yl)indolin-2one (4a).11 Yield: 96 mg (61%) as brown solid; mp: 135−136 °C; 1H NMR (CDCl3, 400 MHz): δ 8.67 (s, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.98−7.91 (m, 2H), 7.44−7.15 (m, 9H), 6.85 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.30−5.28 (m, 1H), 3.79 (s, 1H), 3.56−3.50 (m, 1H), 3.39−3.33 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz): δ 200.4, 178.1, 158.4, 147.6, 140.2, 136.1, 135.7, 133.3, 132.0, 129.3, 128.8, 128.3, 128.1, 127.6, 127.4, 126.0, 125.6, 125.3, 122.1, 111.7, 110.5, 46.5, 45.8, 36.0 ppm. 3-(3-(7-Chloroquinolin-2-yl)-1-oxo-1-phenylpropan-2-yl)indolin-2-one (4b). Yield: 123 mg (72%) as white solid; mp: 163−164 °C; 1H NMR (DMSO-d6, 500 MHz): δ 10.55 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 2H), 7.92 (d, J = 9.0 Hz, 1H), 7.66−7.51 (m, 5H), 7.38 (d, J = 8.5 Hz, 1H), 7.17−7.14 (m, 2H), 6.90−6.82 (m, 2H), 5.14−5.10 (m, 1H), 3.79 (s, 1H), 3.34−3.37 (m, 1H), 3.08−3.03 (m, 1H) ppm; 13C NMR (DMSO-d6, 125 MHz): δ 201.3, 177.6, 160.9, 147.5, 143.5, 136.8, 136.4, 134.2, 133.6, 130.2, 129.3, 128.9, 128.5, 127.2, 127.0, 126.9, 125.4, 125.0, 122.9, 121.6, 109.8, 46.2, 44.9, 35.6 ppm; IR (KBr): 3253, 2965, 1724, 1695, 1473, 1440 cm−1; anal. calcd for C26H19ClN2O2: C, 73.15; H, 4.49; N, 6.56; found: C, 73.26; H, 4.53; N, 6.48. 3-(1-Oxo-3-(quinolin-2-yl)-1-(p-tolyl)propan-2-yl)indolin2-one (4c). Yield: 104 mg (68%) as pale brown solid; mp: 146−147 °C; 1H NMR (CDCl3, 500 MHz): δ 8.99 (s, 1H), 8.13 (d, J = 8.0 Hz, 2H), 7.92−7.88 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.41−7.39 (m, 1H), 7.31− 7.26 (m, 3H), 7.19−7.13 (m, 2H), 7.07−6.99 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.29−5.26 (m, 1H), 3.80 (s, 1H), 3.49−3.47 (m, 1H), 3.23−3.47 (m, 1H), 2.42 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 200.3, 179.0, 158.9, 147.6, 143.9, 141.9, 135.8, 133.5, 129.4, 129.1, 129.0, 128.9, 128.8, 128.7, 128.1, 127.3, 126.8, 126.7, 125.7, 125.1, 122.2, 122.1, 109.8, 46.3, 46.1, 35.7, 21.6 ppm; IR (KBr): 3214, 2953, 1729, 1698, 1483, 1431 cm−1; anal. calcd for C27H22N2O2: C, 79.78; H, 5.46; N, 6.89; found: C, 79.65; H, 5.42; N, 6.94. 3-(3-(7-Chloroquinolin-2-yl)-1-oxo-1-(p-tolyl)propan-2-yl)indolin-2-one (4d). Yield: 117 mg (71%) as pale white solid; mp: 133−139 °C; 1H NMR (CDCl3, 500 MHz): δ 8.13 (d, J = 8.0 Hz, 3H), 7.92−7.88 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.39−7.15 (m, 6H), 7.01 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.5 2942

DOI: 10.1021/acsomega.8b00147 ACS Omega 2018, 3, 2934−2946

Article

ACS Omega

109.1, 49.6, 48.0, 45.8, 11.7 ppm; IR (KBr): 3060, 2924, 1713, 1662, 1466, 1351 cm−1; HRMS (ESI-TOF): m/z calcd for C28H24N2O3 [M + Na]+: 459.1684; found: 459.1683. Methyl 2-Methyl-4-(2-oxoindolin-3-yl)-1,5-diphenyl-1Hpyrrole-3-carboxylate (7d). Yield: 61 mg (73%) as pale solid; mp: 212−213 °C; 1H NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H), 7.32−7.17 (m, 10H), 6.97 (t, J = 7.2 Hz, 2H), 6.91 (t, J = 8.0 Hz, 2H), 4.66 (s, 1H), 3.39 (s, 3H), 2.38 (s, 3H) ppm; 13 C NMR (CDCl3, 100 MHz): δ 180.0, 165.2, 141.1, 138.3, 137.6, 136.3, 131.4, 130.9, 130.7, 129.0, 128.4, 128.2, 128.0, 127.7, 127.3, 123.2, 122.0, 114.9, 110.2, 108.8, 49.8, 45.5, 12.8 ppm; IR (KBr): 3215, 2974, 1714, 1682, 1423, 1364 cm−1; HRMS (ESI-TOF): m/z calcd for C27H22N2O3 [M + Na]+: 445.1528; found: 445.1527. Ethyl 1-Benzyl-4-(5-chloro-2-oxoindolin-3-yl)-2-methyl-5phenyl-1H-pyrrole-3-carboxylate (7e). Yield: 69 mg (81%) as white solid; mp: 208−209 °C; 1H NMR (CDCl3, 500 MHz): δ 8.61 (s, 1H), 7.37−7.13 (m, 6H), 6.95 (d, J = 7.5 Hz, 2H), 6.89−6.81 (m, 5H), 5.05 (s, 2H), 4.50 (s, 1H), 3.96−3.93 (m, 2H), 2.46 (s, 3H), 1.02 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 179.1, 163.7, 140.2, 136.5, 136.4, 135.3, 130.5, 129.6, 128.2, 127.8, 127.6, 127.2, 126.3, 126.1, 124.6, 121.9, 120.9, 113.6, 109.1, 107.9, 57.9, 46.9, 44.7, 13.0, 10.9 ppm; IR (KBr): 2924, 1710, 1649, 1600, 1449, 1361 cm−1; HRMS (ESI-TOF): m/z calcd for C29H25ClN2O3 [M + Na]+: 507.1451; found: 507.1452. Ethyl 4-(5-Chloro-2-oxoindolin-3-yl)-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (7f). Yield: 62 mg (76%) as white solid; mp: 265−266 °C; 1H NMR (CDCl3, 400 MHz): δ 8.46 (s, 1H), 7.32−7.17 (m, 9H), 7.00−6.90 (m, 4H), 4.69 (s, 1H), 3.98−3.89 (m, 2H), 2.38 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H) ppm; 13 C NMR (CDCl3, 100 MHz): δ 180.6, 164.8, 141.5, 138.3, 137.7, 136.3, 131.5, 130.9, 130.8, 128.9, 128.5, 128.1, 128.0, 127.7, 127.2, 123.1, 121.9, 114.8, 110.5, 109.2, 59.0, 45.7, 14.1, 13.0 ppm; IR (KBr): 3264, 2927, 1701, 1613, 1484, 1381 cm−1; HRMS (ESI-TOF): m/z calcd for C28H23ClN2O3 [M + Na]+: 493.1270; found: 493.1274. Methyl 1-Benzyl-4-(5-chloro-2-oxoindolin-3-yl)-2-methyl5-phenyl-1H-pyrrole-3-carboxylate (7g). Yield: 56 mg (68%) as white solid; mp: 256−257 °C; 1H NMR (CDCl3, 500 MHz): δ 8.83 (s, 1H), 7.38−7.34 (m, 5H), 7.29 (t, J = 7.5 Hz, 3H), 7.13 (s, 1H), 6.95−6.88 (m, 4H), 5.06 (s, 2H), 4.51 (s, 1H), 3.40 (s, 3H), 2.45 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 179.8, 165.0, 140.0, 137.8, 137.2, 136.5, 133.2, 130.3, 128.9, 128.8, 128.7, 128.6, 127.4, 127.2, 127.1, 125.6, 123.4, 114.3, 109.9, 109.7, 49.8, 48.1, 45.8, 11.9 ppm; IR (KBr): 3124, 2936, 1716, 1679, 1543, 1264 cm−1; HRMS (ESI-TOF): m/z calcd for C28H23ClN2O3 [M + Na]+: 493.1295; found: 493.1299. Methyl 4-(5-Chloro-2-oxoindolin-3-yl)-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (7h). Yield: 56 mg (70%) as white solid; mp: 276−277 °C; 1H NMR (CDCl3, 500 MHz): δ 8.80 (s, 1H), 7.33−7.22 (m, 9H), 7.14 (d, J = 7.5 Hz, 2H), 6.94 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 4.67 (s, 1H), 3.44 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 180.0, 165.0, 140.0, 138.5, 137.5, 136.4, 133.2, 130.9, 130.5, 129.0, 128.5, 128.3, 128.2, 128.1, 127.9, 127.3, 127.2, 123.5, 114.3, 109.9, 49.9, 45.7, 12.9 ppm; IR (KBr): 3315, 3122, 1704, 1683, 1452, 1298 cm −1 ; HRMS (ESI-TOF): m/z calcd for C27H21ClN2O3 [M + Na]+: 479.1138; found: 479.1138. Methyl 4-(5-Fluoro-2-oxoindolin-3-yl)-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (7i). Yield: 64 mg (79%) as pale white solid; mp: 220−221 °C; 1H NMR (CDCl3, 500 MHz): δ 8.95 (s, 1H), 7.34−7.22 (m, 9H), 6.85 (s, 2H), 6.74−

Hz, 1H), 5.29−5.25 (m, 1H), 3.81 (s, 1H), 3.51−3.46 (m, 1H), 3.24−3.21 (m, 1H), 2.45 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 200.1, 178.4, 160.1, 148.0, 144.1, 141.5, 135.6, 134.9, 133.3, 129.5, 128.9, 128.7, 128.5, 128.2, 128.0, 126.8, 126.7, 125.1, 122.3, 122.2, 109.5, 46.0, 45.8, 35.6, 21.7 ppm; IR (KBr): 3233, 2987, 1731, 1706, 1477, 1421 cm−1; anal. calcd for C27H21ClN2O2: C, 73.55; H, 4.80; N, 6.35; found: C, 73.45; H, 4.85; N, 6.29. 5-Chloro-3-(1-oxo-1-phenyl-3-(quinolin-2-yl)propan-2-yl)indolin-2-one (4e). Yield: 84 mg (56%) as white solid; mp: 183−184 °C; 1H NMR (CDCl3, 400 MHz): δ 9.12 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.87 (d, J = 4.4 Hz, 1H), 7.69−7.50 (m, 3H), 7.40−7.28 (m, 3H), 7.20− 7.17 (m, 2H), 7.02 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.33−5.31 (m, 1H), 3.82 (s, 1H), 3.35−3.50 (m, 1H), 3.25−3.20 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz): δ 200.4, 178.4, 158.4, 147.6, 140.2, 136.1, 135.7, 133.3, 132.0, 129.3, 128.8, 128.3, 128.1, 127.6, 127.4, 126.0, 125.6, 125.3, 122.1, 111.7, 110.5, 46.5, 45.8, 36.0 ppm; IR (KBr): 3227, 2941, 1729, 1687, 1473, 1438 cm−1; anal. calcd for C26H19ClN2O2: C, 73.15; H, 4.49; N, 6.56; found: C, 73.26; H, 4.45; N, 6.62. 3-(3-(7-Chloroquinolin-2-yl)-1-oxo-1-phenylpropan-2-yl)1-methylindolin-2-one (4f). Yield: 109 mg (66%) as brown solid; mp: 117−118 °C; 1H NMR (CDCl3, 400 MHz): δ 8.24 (d, J = 7.2 Hz, 1H), 7.93−7.89 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.63−7.30 (m, 7H), 7.12 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 5.36−5.31 (m, 1H), 3.80 (s, 1H), 3.52−3.46 (m, 1H), 3.46−3.27 (m, 1H), 3.06 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 200.8, 176.4, 158.7, 147.6, 144.5, 136.0, 135.7, 133.1, 129.7, 128.9, 128.8 (2C), 128.4, 128.2 (2C), 127.3, 126.7, 126.2, 128.8, 124.8, 122.3, 122.0, 107.9, 46.2, 45.5, 35.9, 26.1 ppm; IR (KBr): 3202, 2932, 1726, 1619, 1469, 1423 cm−1; anal. calcd for C27H21ClN2O2: C, 73.55; H, 4.80; N, 6.35; found: C, 73.65; H, 4.76; N, 6.28. Ethyl 2-Methyl-4-(2-oxoindolin-3-yl)-1,5-diphenyl-1H-pyrrole-3-carboxylate (7a).14 Yield: 65 mg (75%) as pale white solid; mp: 231−232 °C; 1H NMR (CDCl3, 500 MHz): δ 8.89 (s, 1H), 7.32−7.17 (m, 10H), 6.96−6.93 (m, 4H), 4.69 (s, 1H), 4.00−3.86 (m, 2H), 2.39 (s, 3H), 0.99 (t, J = 9.0 Hz, 3H) ppm; 13 C NMR (CDCl3, 125 MHz): δ 180.6, 164.8, 141.5, 138.3, 137.7, 136.3, 131.5, 130.9, 130.8, 128.9, 128.5, 128.1, 128.0, 127.7, 127.2, 123.1, 121.9, 114.8, 110.5, 109.2, 59.0, 45.7, 14.1, 13.0 ppm; HRMS (ESI-TOF): m/z calcd for C28H24N2O3 [M + Na]+: 459.1684; found: 459.1685. Ethyl 1-Benzyl-2-methyl-4-(2-oxoindolin-3-yl)-5-phenyl1H-pyrrole-3-carboxylate (7b).14 Yield: 64 mg (71%) as pale white solid; mp: 210−211 °C; 1H NMR (CDCl3, 400 MHz): δ 8.26 (s, 1H), 7.36−7.30 (m, 7H), 7.18−7.14 (m, 3H), 6.95 (d, J = 8.8 Hz, 4H), 5.00 (s, 2H), 4.53 (s, 1H), 3.93−3.90 (m, 2H), 2.45 (s, 3H), 0.97 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 180.2, 164.8, 141.3, 137.5, 137.4, 136.3, 131.6, 130.6, 128.8, 128.6, 128.3, 128.1, 127.3, 127.2, 125.6, 123.0, 121.9, 114.7, 110.1, 109.0, 58.9, 48.0, 45.7, 14.1, 12.0 ppm; HRMS (ESI-TOF): m/z calcd for C29H26N2O3 [M + Na]+: 473.1841; found: 473.1840. Methyl 1-Benzyl-2-methyl-4-(2-oxoindolin-3-yl)-5-phenyl1H-pyrrole-3-carboxylate (7c). Yield: 60 mg (69%) as pale white solid; mp: 201−202 °C; 1H NMR (CDCl3, 500 MHz): δ 9.01 (s, 1H), 7.36−7.26 (m, 8H), 7.16 (t, J = 5.5 Hz, 1H), 6.95−6.94 (m, 5H), 5.07 (s, 2H), 4.55 (s, 1H), 3.35 (s, 3H), 2.45 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 180.7, 165.2, 141.5, 137.7, 137.4, 136.3, 131.5, 131.3, 130.6, 128.8, 128.7, 128.6, 127.3, 127.2, 125.6, 122.9, 121.9, 114.9, 109.9, 2943

DOI: 10.1021/acsomega.8b00147 ACS Omega 2018, 3, 2934−2946

Article

ACS Omega

1263 cm−1; HRMS (ESI-TOF): m/z calcd for C29H26N2O3 [M + H]+: 473.1833; found: 473.1842. Ethyl 1-Benzyl-5-(4-methoxyphenyl)-2-methyl-4-(2-oxoindolin-3-yl)-1H-pyrrole-3-carboxylate (7o). Yield: 53 mg (65%) as pale white solid; mp: 189−190 °C; 1H NMR (CDCl3, 500 MHz): δ 8.49 (s, 1H), 7.36−7.16 (m, 5H), 6.96− 6.89 (m, 8H), 5.05 (s, 2H), 4.53 (s, 1H), 3.92−3.89 (m, 2H), 3.79 (s, 3H), 2.45 (s, 3H), 0.95 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 164.8, 159.8, 141.4, 137.5, 137.3, 136.0, 132.6, 131.7, 128.8, 128.6, 127.3, 127.1, 125.6, 122.9, 122.8, 121.8, 114.6, 114.1, 110.0, 109.1, 58.9, 55.2, 47.9, 45.9, 14.0, 11.9 ppm; IR (KBr): 3194, 2874, 1726, 1664, 1489, 1245 cm−1; HRMS (ESI-TOF): m/z calcd for C30H28N2O4 [M + Na]+: 503.1947; found: 503.1948. Methyl 1-Butyl-4-(5-chloro-2-oxoindolin-3-yl)-2-methyl-5phenyl-1H-pyrrole-3-carboxylate (7p). Yield: 52 mg (68%) as pale brown solid; mp: 158−159 °C; 1H NMR (CDCl3, 500 MHz): δ 8.54 (s, 1H), 7.54−7.44 (m, 4H), 7.21 (s, 1H), 7.10 (s, 1H), 6.84−6.79 (m, 2H), 4.39 (s, 1H), 3.77 (t, J = 7.5 Hz, 2H), 3.38 (s, 3H), 2.57 (s, 3H), 1.53−1.47 (m, 2H), 1.21−1.18 (m, 2H), 0.79 (t, J = 8.0 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 179.8, 165.0, 139.9, 137.1, 135.6, 133.3, 131.9, 131.5, 130.9, 128.7, 127.1, 127.0, 13.4, 114.0, 109.7, 108.9, 49.6, 45.7, 44.2, 32.6, 19.8, 13.4, 11.7 ppm; IR (KBr): 3255, 2919, 1795, 1708, 1563, 1489 cm−1; HRMS (ESI-TOF): m/z calcd for C25H25ClN2O3 [M + Na]+: 459.1451; found: 459.1458. Ethyl 1-Butyl-2-methyl-4-(2-oxoindolin-3-yl)-5-phenyl-1Hpyrrole-3-carboxylate (7q).14 Yield: 57 mg (69%) as pale white solid; mp: 175−176 °C; 1H NMR (CDCl3, 500 MHz): δ 9.03 (s, 1H), 7.53−7.41 (m, 5H), 7.10 (d, J = 7.0 Hz, 2H), 6.86−6.78 (m, 2H), 4.39 (s, 1H), 3.93−3.89 (m, 2H), 3.78− 3.76 (m, 2H), 2.58 (s, 3H), 1.55−1.21 (m, 2H), 1.20−1.16 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 180.1, 164.7, 140.2, 136.9, 135.6, 133.4, 131.4, 131.0, 128.6, 127.0, 123.3, 113.9, 110.0, 109.3, 58.8, 45.8, 44.2, 32.7, 19.8, 14.1, 13.4, 11.9 ppm. Methyl 1-Benzyl-5-cyclohexyl-2-methyl-4-(2-oxoindolin-3yl)-1H-pyrrole-3-carboxylate (7r). Yield: 47 mg (54%) as pale white solid; mp: 168−169 °C; 1H NMR (CDCl3, 500 MHz): δ 8.59 (s, 1H), 7.39−7.28 (m, 3H), 7.19 (d, J = 7.5 Hz, 1H), 7.01−6.92 (m, 5H), 5.16 (s, 2H), 4.98 (s, 1H), 3.35 (s, 3H), 2.75−2.63 (m, 1H), 2.45 (s, 3H), 1.91−1.87 (m, 2H), 1.80− 1.58 (m, 8H) ppm; 13C NMR (CDCl3, 100 MHz): δ 180.2, 165.2, 141.5, 138.0, 137.3, 131.5, 128.9, 128.7, 127.5, 127.2, 125.6, 125.4, 123.0, 121.9, 112.5, 108.9, 65.8, 49.5, 45.5, 36.5, 33.3, 27.3, 25.3, 11.7 ppm; IR (KBr): 3273, 2932, 1705, 1618, 1530, 1445 cm −1 ; HRMS (ESI-TOF): m/z calcd for C28H30N2O3 [M + Na]+: 465.2154; found: 465.2153. Ethyl 1-Benzyl-2-methyl-4-(2-oxoindolin-3-yl)-5-propyl1H-pyrrole-3-carboxylate (7s). Yield: 56 mg (57%) as pale brown solid; mp: 179−180 °C; 1H NMR (CDCl3, 500 MHz): δ 8.19 (s, 1H), 7.39−7.29 (m, 4H), 7.19 (t, J = 7.5 Hz, 1H), 6.99−6.91 (m, 4H), 5.15 (s, 2H), 4.65 (s, 1H), 3.92−3.88 (m, 2H), 2.65−2.58 (m, 2H), 2.42 (s, 3H), 1.55−1.50 (m, 2H), 0.98−0.93 (m, 6H) ppm; 13C NMR (CDCl3, 100 MHz): δ 179.9, 164.8, 141.5, 137.1, 136.7, 133.9, 131.4, 128.9, 128.8, 127.5, 127.2, 125.5, 125.4, 123.0, 121.9, 113.0, 109.5, 109.0, 58.8, 47.0, 45.3, 26.5, 24.7, 14.1, 14.0, 11.7 ppm; IR (KBr): 3253, 2926, 1719, 1495, 1209, 1120 cm−1; HRMS (ESI-TOF): m/z calcd for C26H28N2O3 [M + Na]+: 439.1997; found: 439.1992. Methyl 1-Benzyl-2-methyl-4-(1-methyl-2-oxoindolin-3-yl)5-phenyl-1H-pyrrole-3-carboxylate (7t). Yield: 58 mg (65%)

6.70 (m, 2H), 4.67 (s, 1H), 3.41 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 180.4, 165.1, 158.9 (d, J = 239.8 Hz, 1C-F), 138.5, 137.5, 136.4, 130.9, 130.5, 129.2, 129.0, 128.5, 128.2, 128.1, 127.8, 127.5, 127.0, 118.5, 115.1, 114.4, 110.0, 49.8, 46.1, 12.8 ppm; IR (KBr): 3253, 2924, 1714, 1659, 1613, 1479 cm −1 ; HRMS (ESI-TOF): m/z calcd for C27H21FN2O3 [M + Na]+: 463.1434; found: 464.1443. Ethyl 4-(7-Fluoro-2-oxoindolin-3-yl)-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (7j). Yield: 52 mg (62%) as white solid; mp: 225−226 °C; 1H NMR (CDCl3, 400 MHz): δ 7.85 (s, 1H), 7.28−7.21 (m, 9H), 6.99−6.90 (m, 3H), 6.81 (d, J = 7.6 Hz, 1H), 4.70 (s, 1H), 4.00−3.94 (q, 2H), 2.38 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 179.1, 164.7, 146.2 (d, J = 253 Hz, 1C-F), 145.5, 138.3, 137.6, 136.3, 134.3, 134.2, 130.9, 130.6, 128.7, 128.6, 128.4, 128.1, 127.8, 127.2, 122.5, 122.4, 118.9, 114.4, 114.3, 114.2, 110.5, 59.1, 45.8, 14.1, 13.0 ppm; IR (KBr): 3202, 3046, 1716, 1644, 1496, 1444 cm −1 ; HRMS (ESI-TOF): m/z calcd for C28H23FN2O3 [M + Na]+: 477.1590; found: 477.1593. Ethyl 4-(7-Fluoro-2-oxoindolin-3-yl)-2-methyl-5-phenyl-1(p-tolyl)-1H-pyrrole-3-carboxylate (7k). Yield: 55 mg (63%) as pale white solid; mp: 235−236 °C; 1H NMR (CDCl3, 500 MHz): δ 7.99 (s, 1H), 7.26−7.01 (m, 9H), 6.98−6.89 (m, 2H), 6.79 (d, J = 7.5 Hz, 1H), 4.69 (s, 1H), 3.99−3.93 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 1.04 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 178.8, 164.8, 146.4 (d, J = 247 Hz, 1CF), 138.3, 138.0, 138.2, 136.4, 135.0, 132.0, 130.9, 128.8, 128.7, 128.2, 128.1, 127.7, 120.2, 118.9, 114.2, 114.1, 110.3, 59.1, 45.8, 21.0, 14.1, 12.9 ppm; IR (KBr): 3149, 3032, 2924, 1722, 1652, 1450 cm−1; HRMS (ESI-TOF): m/z calcd for C29H25FN2O3 [M + Na]+: 491.1747; found: 491.1749. Ethyl 1-Benzyl-4-(7-fluoro-2-oxoindolin-3-yl)-2-methyl-5phenyl-1H-pyrrole-3-carboxylate (7l). Yield: 57 mg (66%) as pale white solid; mp: 231−232 °C; 1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.36−7.30 (m, 7H), 6.96−6.92 (m, 5H), 6.75 (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 4.55 (s, 1H), 3.96−3.94 (m, 2H), 2.45 (s, 3H), 1.02 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 178.6, 164.7, 148.3 (d, J = 239 Hz, 1CF), 137.6, 137.3, 136.4, 135.2, 134.3, 130.4, 128.8, 128.7, 128.6, 125.6, 122.4, 122.3, 118.8, 114.3, 114.3, 114.2, 110.0, 59.0, 48.0, 45.8, 14.1, 12.0 ppm; IR (KBr): 3205, 2926, 1719, 1593, 1461, 1209 cm−1; HRMS (ESI-TOF): m/z calcd for C29H25FN2O3 [M + H]+: 469.1927; found: 469.1930. Methyl 4-(7-Fluoro-2-oxoindolin-3-yl)-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (7m). Yield: 54 mg (64%) as pale white solid; mp: 238−239 °C; 1H NMR (CDCl3, 400 MHz): δ 8.97 (s, 1H), 7.33−7.17 (m, 9H), 6.85 (s, 2H), 6.71 (d, J = 8.8 Hz, 2H), 4.67 (s, 1H), 3.42 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 180.5, 165.1, 158.5 (d, J = 263 Hz, 1C-F), 138.5, 137.5, 136.4, 133.2, 133.1, 130.9, 130.5, 129.2, 129.0, 128.4, 128.3, 128.2, 127.9, 118.5, 115.1, 114.4, 110.0, 49.9, 46.1, 12.9 ppm; IR (KBr): 3207, 2970, 1720, 1643, 1504, 1262 cm−1; HRMS (ESI-TOF): m/z calcd for C27H21FN2O3 [M + H]+: 441.1614; found: 441.1613. Methyl 1-Benzyl-2-methyl-4-(2-oxoindolin-3-yl)-5-(ptolyl)-1H-pyrrole-3-carboxylate (7n). Yield: 56 mg (66%) as pale white solid; mp: 226−227 °C; 1H NMR (CDCl3, 400 MHz): δ 9.29 (s, 1H), 7.37−7.29 (m, 8H), 7.18−7.16 (m, 5H), 5.07 (s, 2H), 4.56 (s, 1H), 3.36 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 180.9, 165.2, 141.5, 138.5, 137.6, 137.5, 136.3, 131.6, 129.4, 128.8, 128.6, 127.6, 127.3, 127.2, 125.6, 122.9, 121.8, 114.8, 109.8, 109.1, 49.6, 47.9, 45.8, 21.2, 11.7 ppm; IR (KBr): 3145, 2967, 1704, 1683, 1402, 2944

DOI: 10.1021/acsomega.8b00147 ACS Omega 2018, 3, 2934−2946

Article

ACS Omega as white solid; mp: 162−163 °C; 1H NMR (CDCl3, 500 MHz): δ 7.35−7.21 (m, 8H), 6.75−6.94 (m, 4H), 6.84 (d, J = 7.5 Hz, 2H), 5.07 (s, 2H), 4.49 (s, 1H), 3.31 (s, 3H), 3.25 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 178.0, 165.1, 144.2, 137.6, 137.4, 136.2, 130.8, 130.6, 128.8, 128.7, 128.6 (2), 127.3, 127.2, 125.6, 122.6, 122.0, 115.0, 109.8, 107.1, 49.8, 48.0, 45.2, 32.0, 11.7 ppm; IR (KBr): 3016, 2944, 1703, 1610, 1454, 1356 cm−1; HRMS (ESI-TOF): m/z calcd for C29H26N2O3 [M + H]+: 451.2022; found: 451.2018. Ethyl 1-Benzyl-4-(5-chloro-2-oxoindolin-3-yl)-2,5-diphenyl-1H-pyrrole-3-carboxylate (7u). Yield: 55 mg (58%) as pale brown solid; mp: 248−149 °C; 1H NMR (CDCl3, 500 MHz): δ 8.01 (s, 1H), 7.36−7.31 (m, 10H), 7.16−7.10 (m, 4H), 6.94 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.48 (s, 2H), 4.95 (s, 2H), 4.52 (s, 1H), 3.76−3.72 (m, 2H), 0.07 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 180.1, 164.0, 141.5, 140.1, 137.9, 131.3, 130.7, 130.6, 130.0, 128.8, 128.6, 128.3 (2), 128.2, 127.6, 127.4, 127.3, 127.0, 126.1, 125.7, 123.0, 121.9, 116.0, 109.2, 59.0, 48.6, 45.5, 13.5 ppm; IR (KBr): 3266, 2982, 1706, 1609, 1488, 1218 cm−1; HRMS (ESI-TOF): m/z calcd for C34H27ClN2O3 [M + Na]+: 569.1608; found: 569.1607. 3-(4-Acetyl-5-methyl-1,2-diphenyl-1H-pyrrol-3-yl)indolin2-one (7v).14 Yield: 52 mg (64%) as pale white solid; mp: 238−239 °C; 1H NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H), 7.34−7.10 (m, 11H), 6.94 (t, J = 8.4 Hz, 3H), 4.62 (s, 1H), 2.38 (s, 3H), 2.33 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 192.3, 177.9, 146.2, 140.1, 139.0, 138.7, 137.6, 133.4, 132.8, 130.3, 130.1, 129.8, 129.2, 128.6, 128.0, 124.3, 121.2, 120.0, 119.8, 111.3, 47.6, 33.4, 12.1 ppm. 3-(1-Benzyl-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-one (7w). Yield: 34 mg (37%) as pale brown solid; mp: 212−213 °C; 1H NMR (CDCl3, 500 MHz): δ 8.23 (s, 1H), 7.37−7.27 (m, 9H), 6.94−6.89 (m, 5H), 5.12 (s, 2H), 4.49 (s, 1H), 2.51−2.46 (m, 2H), 2.21−2.16 (m, 2H), 1.04 (s, 3H), 0.95 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz): δ 192.7, 179.2, 143.4, 142.3, 137.3, 137.2, 130.9, 130.6, 129.9, 128.9, 128.8, 128.7, 127.9, 127.5, 125.6, 124.6, 122.9, 121.6, 116.7, 113.8, 109.2, 51.7, 47.9, 44.7, 43.4, 35.2, 28.1 ppm; IR (KBr): 3145, 3015, 2914, 1709, 1647, 1232 cm−1; HRMS (ESI-TOF): m/z calcd for C31H28N2O2 [M + H]+: 461.2228; found: 461.2226. 3-(4-Oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-one (7x). Yield: 34 mg (41%) as white solid; mp: 192−193 °C; 1H NMR (CDCl3, 500 MHz): δ 7.96 (s, 1H), 7.37−7.33 (m, 3H), 7.27−6.99 (m, 8H), 6.96−6.92 (m, 3H), 4.66 (s, 1H), 2.68−2.64 (m, 2H), 2.39−2.36 (m, 2H), 2.07− 2.02 (m, 2H) ppm; 13C NMR (CDCl3, 100 MHz): δ 193.6, 179.1, 145.1, 142.2, 137.2, 136.9, 130.7, 130.4, 130.1, 129.0, 128.3, 128.0, 127.9, 127.7, 127.6, 123.2, 121.6, 118.0, 114.0, 109.2, 44.6, 37.8, 23.4, 23.1 ppm; IR (KBr): 3255, 3102, 2925, 1712, 1652, 1464 cm−1; HRMS (ESI-TOF): m/z calcd for C28H22N2O2 [M + H]+: 419.1760; found: 419.1756. Ethyl 4-(2-Oxoindolin-3-yl)-1,5-diphenyl-1H-pyrrole-3-carboxylate (7y). Yield: 49 mg (58%) as white solid; mp: 159− 160 °C; 1H NMR (CDCl3, 400 MHz): δ 8.64 (s, 1H), 7.46 (s, 1H), 7.14−7.09 (m, 7H), 7.01−6.97 (m, 4H), 6.81−6.73 (m, 3H), 4.53 (s, 1H), 3.83−3.78 (q, 2H), 0.86 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 179.8, 163.8, 141.8, 139.2, 136.5, 131.0, 130.9, 129.2, 129.0, 128.4, 128.1, 127.4, 127.3, 125.5, 123.1, 121.8, 116.7, 115.1, 114.5, 109.3, 59.5, 45.2, 14.1 ppm; IR (KBr): 3315, 2964, 1717, 1471, 1447, 1238 cm−1; HRMS (ESI-TOF): m/z calcd for C27H22N2O3 [M + H]+: 423.1709; found: 423.1704.

Computational Details. All of the calculations were performed using Gaussian 09 package 2. The geometries of all of the structures were optimized using HF level theory and 3-21g basis set. The single-point energies and NBO charges were calculated using 6-31g(d,p) basis set with B3LYP-level density functional theory.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b00147. Computational details, and copies of 1H and 13C spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Srinivasarao Yaragorla: 0000-0001-6152-5861 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge UPE-2 and CSIR No. 02/200/ EMRII for the financial support. R.D. and R.P. acknowledge Central University of Rajasthan and CSIR for the fellowships, respectively.

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REFERENCES

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DOI: 10.1021/acsomega.8b00147 ACS Omega 2018, 3, 2934−2946

Article

ACS Omega

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DOI: 10.1021/acsomega.8b00147 ACS Omega 2018, 3, 2934−2946